title: DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism.
abstract: The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.
authors.affiliation: Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Xuyu
authors.initials: X
authors.lastname: Yang
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Popescu
authors.forename: Drazen B
authors.initials: DB
authors.lastname: Zimonjic
mesh_terms: D020816:Amino Acid Motifs; D017306:Annexin A2 / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D009418:S100 Proteins / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D020690:GTPase-Activating Proteins; D010958:Plasminogen; D009418:S100 Proteins; D025521:Tumor Suppressor Proteins; D000099248:S100 Calcium Binding Protein A10; C472822:ANXA2 protein, human; C112352:DLC1 protein, human